Submissions for variant NM_000059.4(BRCA2):c.7884dup (p.Trp2629fs)

dbSNP: rs397507943

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000225658	SCV000282451	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000225658	SCV000327757	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496429	SCV004847869	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Trp2629MetfsX12 variant in BRCA2 has not been previously reported in individuals with hereditary breast and/or ovarian cancer (HBOC) and was absent from large population studies, but has been reported in ClinVar (Variation ID: 52431). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2629 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496429	SCV005835601	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2629Metfs*12) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 29371908). This variant is also known as c.7884dupA (p.Trp2629Metfs). ClinVar contains an entry for this variant (Variation ID: 52431). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496429	SCV000587919	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research